Cyclopropene derivatives

ABSTRACT

The cyclopropene derivatives of the present invention are useful as the intermediates for producing cyclopropenone derivatives exhibiting strong inhibition activity of thiol protease such as calpain, papain, cathepsin B, cathepsin H, cathepsin L and the like.

FIELD OF THE INVENTION

The present invention relates to novel cyclopropene derivatives, andmore specifically, the present invention relates to novel cyclopropenederivatives useful as intermediates for the production of cyclopropenonederivatives having strong inhibitory activity against thiol proteasesuch as calpain, papain, cathepsin B, cathepsin H, cathepsin L and thelike, or the salts thereof.

BACKGROUND OF THE INVENTION

As the biological action of thiol protease such as calpain, papain,cathepsin B, cathepsin H, cathepsin L. etc. has been elucidated, it hasbeen found that the abnormal increase thereof is the cause of variousdiseases, so that the inhibitors of thiol protease have been used astheir therapeutical agents of those diseases. For example,, reports havebeen issued that calpain inhibitors have effects on animal models withmuscular dystrophy, cataract, myocardial infarction, delayed death ofneurocytes after brain infarction, and the like, while cathepsininhibitors have effects on cancer metastasis, amyotrophy, osteoporosisand the like. However, because known inhibitors of thiol proteases, suchas peptidyl aldehydes, epoxy succinate derivatives, etc., are poor inoral administration, tissue distribution, and cell membranepermeability, expectation has been toward the development of novel thiolprotease inhibitors which can overcome these problems.

SUMMARY OF THE INVENTION

Thus, the present inventors have made investigations of the intermediatefor the production of a thiol protease inhibitor showing excellent oraladministration, tissue distribution, and cell membrane permeability.Then, the inventors have achieved the present invention.

The present invention resides in cyclopropene derivatives represented bythe general formula (I): ##STR1## [In the above general formula (I), R¹represents hydrogen atom or a protective group of amino group; R²represents hydrogen atom, a protective group of amino group or C₁ -C₅alkyl group; or when R¹ and R² are taken together, they representphthaloyl group; R⁴ and R⁶ independently represent hydrogen atom or C₁-C₅ alkyl group; R³ and R⁵ independently represent hydrogen atom or C₁-C₁₅ alkyl group optionally substituted with C₃ -C₁₀ cycloalkyl group orC₆ -C₁₀ aryl group; or when R⁵ and R⁶ are taken together, they representC₂ -C₆ alkylene group; R⁷ and R⁸ represent --OR¹⁰ and --OR¹¹,respectively (wherein R¹⁰ and R¹¹ independently represent C₁ -C₅ alkylgroup optionally substituted with phenyl group: or when R¹⁰ and R¹¹ aretaken together, they represent C₂ -C₆ alkylene group optionallysubstituted with one or more C₁ -C₅ alkyl groups); or when R⁷ and R⁸ aretaken together, they represent ═O; R⁹ represents hydrogen atom, C₁ -C₁₅alkyl group, C₃ -C₁₀ cycloalkyl group, C₂ -C₁₅ alkenyl group, C₆ -C₁₀aryl group optionally substituted with a substituent, heterocyclic groupoptionally substituted with a substituent, or --CR¹² R¹³ OH (wherein R¹²and R¹³ independently represent hydrogen atom, C₁ -C₁₅ alkyl group or C₆-C₁₀ aryl group; or when R¹² and R¹³ are taken together to form C₃ -C₁₀cycloalkyl group); and n represents 0 or 1, provided that when nrepresents 1, R⁷,when taken together with R⁸ does not represent ═O], andthe salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be explained in details. The compound ofthe present invention is cyclopropene derivatives represented by thegeneral formula (I): ##STR2## [In the above general formula (I), R¹represents hydrogen atom or a protective group of amino group(urethane-type protective group such as methoxycarbonyl group,tert-butoxycarbonyl group, benzyloxycarbonyl group,4-methoxybenzyloxycarbonyl group, 4-chlorobenzyloxycarbonyl group,3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonylgroup, 9-fluorenylmethoxycarbonyl group, etc.; acyl-type protectivegroup such as formyl group, trifluoroacetyl group, p-toluene sulfonylgroup, 2,4,6-trimethylbenzene sulfonyl group, benzoyl group,chloroacetyl group, etc.; alkyl-type protective group such as benzylgroup, diphenylmethyl group, trityl group, etc.); R² represents hydrogenatom, a protective group of amino group (which is as defined for R¹) orC₁ -C₅ alkyl group (methyl group, propyl group, pentyl group, etc.); orwhen R¹ and R² are taken together, they represent phthaloyl group; R⁴and R⁶ independently represent hydrogen atom or C₁ -C₅ alkyl group(methyl group, propyl group, pentyl group, etc.); R³ and R⁵independently represent hydrogen atom or C₁ -C₁₅ alkyl group (methylgroup, hexyl group, decyl group, pentadecyl group, etc.) optionallysubstituted with C₃ -C₁₀ cycloalkyl group (cyclopropyl group,cyclopentyl group, cyclodecyl group, etc.) or C₆ -C₁₀ aryl group (phenylgroup, naphtyl group, etc.); or when R⁵ and R⁶ are taken together, theyrepresent C₂ -C₆ alkylene group (ethylene group, tetramethylene group,hexamethylene group, etc.); R⁷ and R⁸ represent --OR¹⁰ and --OR¹¹,respectively (wherein R¹⁰ and R¹¹ independently represent C₁ -C₅ alkylgroup (methyl group, propyl group, pentyl group, etc.) optionallysubstituted with phenyl group; or when R¹⁰ and R¹¹ are taken together,they represent C₂ -C₆ alkylene group (ethylene group, tetramethylenegroup, hexamethylene group, etc.) optionally substituted with one ormore C₁ -C₅ alkyl groups (methyl group, propyl group, pentyl group,etc.); or when R⁷ and R⁸ are taken together, they represent ═O; R⁹represents hydrogen atom; C₁ -C₁₅ alkyl group (methyl group, hexylgroup, decyl group, pentadecyl group, etc.); C₃ -C₁₀ cycloalkyl group(cyclopropyl group, cyclopentyl group, cyclodecyl group, etc.); C₂ -C₁₅alkenyl group (vinyl group, hexenyl group, undecenyl group, pentadecenylgroup, etc.); C₆ -C₁₀ aryl group (phenyl group, naphtyl group, etc.)optionally substituted with one or more substituents selected from thegroup consisting of halogen atom (fluorine atom, chlorine atom, bromineatom, iodine atom, etc.), C₁ -C₅ alkyl group (methyl group, propylgroup, pentyl group, etc.), hydroxyl group and C₁ -C₅ alkoxy group(methoxy group, propoxy group, pentyloxy group, etc.); a heterocyclicgroup having one to four hetero atoms selected from the group consistingof oxygen atom, sulfur atom and nitrogen atom with the total number ofthe atoms constituting the ring being in the range of from 5 to 10(furane ring, thiophene ring, pyridine ring, pyridine oxide ring,pyrimidine ring, pyridazine ring, benzofurane ring, benzothiophene ring,quinoline ring, naphthyridine ring, etc.), and optionally substitutedwith one or more substituents selected from the group consisting of C₃-C₁₂ trialkylsilyl group (trimethylsilyl group, triethylsilyl group,tert-butyldimethylsilyl group, etc.), halogen atom (fluorine atom,chlorine atom, bromine atom, iodine atom, etc.), C₁ -C₅ alkyl group(methyl group, propyl group, pentyl group, etc.), hydroxyl group and C₁-C₅ alkoxy group (methoxy group, propoxy group, pentyloxy group, etc.);or --CR¹² R¹³ OH (wherein R¹² and R¹³ independently represent hydrogenatom, C₁ -C₁₅ alkyl group (methyl group, hexyl group, decyl group,pentadecyl group, etc.) or C₆ -C₁₀ aryl group (phenyl group, naphthylgroup, etc.); or when R¹² and R¹³ are taken to form C₃ -C₁₀ cycloalkylgroup (cyclopropyl group, cyclopentyl group, cyclodecyl group, etc.);and n represents 0 or 1, provided that when n represents 1, R⁷, whentaken together with R⁸ does not represent ═O], and the salt thereof.

Particularly preferable is a compound of the formula (I) in which R¹represents hydrogen atom, tert-butoxycarbonyl group, benzyloxycarbonylgroup, methoxycarbonyl group, 9-fluorenylmethoxycarbonyl group,p-toluene sulfonyl group, or trityl group; R², R⁴ and R⁶ independentlyrepresent hydrogen atom or C₁ -C₃ alkyl group; or when R¹ and R² aretaken together, they represent phthaloyl group; R³ and R⁵ independentlyrepresent hydrogen atom or C₁ -C₅ alkyl group optionally substitutedwith C₁ -C₅ cycloalkyl group, phenyl group or naphtyl group; or R⁵, whentaken together with R⁶ represents C₃ -C₆ cycloalkyl group; R⁷ and R⁸represent-OR¹⁰ and --OR¹¹, respectively (wherein R¹⁰ and R¹¹independently represent C₁ -C₃ alkyl group optionally substituted withphenyl group; or R¹⁰, when taken together with R¹¹ represents C₂ -C₄alkylene group optionally substituted with one or more C₁ -C₃ alkylgroups; or R⁷,when taken together with R⁸ represents ═O;R⁹ representshydrogen atom; C₁ -C₆ alkyl group; C₃ -C₈ cycloalkyl group; C₂ -C₈alkenyl group; phenyl group or naphtyl group each optionally substitutedwith one or more substituents selected from the group consisting ofhalogen atom, C₁ -C₅ alkyl group and C₁ -C₅ alkoxy group; heterocyclicgroup having one to four hetero atoms selected from the group consistingof oxygen atom, sulfur atom and nitrogen atom with the total number ofthe atoms constituting the ring being in the range of from 5 to 10, andoptionally substituted with one or more substituents selected from thegroup consisting of halogen atom, C₁ -C₅ alkyl group, C₁ -C₅ alkoxygroup and C₃ -C₁₂ trialkylsilyl group; or --CR¹² R¹³ OH (wherein R¹² andR¹³ independently represent hydrogen atom, C₁ -C₃ alkyl group or phenylgroup); and n represents 0 or 1, provided that when n represents 1, R⁷,when taken together with R⁸ does not represent ═O.

Most preferable is a compound of the formula (I) in which R¹ representshydrogen atom, tert-butoxycarbonyl group, benzyloxycarbonyl group ormethoxycarbonyl group; R², R⁴ and R⁶ independently represent hydrogenatom or C₁ -C₃ alkyl group; R³ and R⁵ independently represent hydrogenatom or C₁ -C₅ alkyl group optionally substituted with phenyl group; R⁷and R⁸ represent --OR¹⁰ and --OR¹¹, respectively (wherein R¹⁰, whentaken together with R¹¹ represents C₂ -C₄ alkylene group optionallysubstituted with one or more substituents selected from C₁ -C₃ alkylgroups; or R⁷, when taken together with R⁸ represents ═O; R⁹ representshydrogen atom; C₁ -C₆ alkyl group; C₂ -C₈ alkenyl group; phenyl groupoptinally substituted with one or more substituents selected from thegroup consisting of halogen atom and C₁ -C₅ alkyl group; furyl group orthienyl group each optionally substituted with one or more C₃ -C₁₂trialkylsilyl groups; or --CR¹² R¹³ OH (wherein R¹² and R¹³independently represent hydrogen atom, C₁ -C₃ alkyl group or phenylgroup); and n represents 0 or 1, provided that when n represents 1, R⁷,when taken together with R⁸ does not represent ═O.

The asymmetric carbons present in the cyclopropene derivativesrepresented by the above general formula (I) independently form (R), (S)or (RS) configuration.

Specific examples of the compounds in accordance with the presentinvention are shown in tables. Table 1 shows the compounds wherein R⁷and R⁸ represent --OR¹⁰ and --OR¹¹, respectively, and n is zero; Table 2shows the compounds wherein R⁷,taken together with R⁸ represents ═O, andn is zero; Table 3 shows the compounds wherein n is one and R⁷ and R⁸represent --OR¹⁰ and --OR¹¹, respectively. In the Tables 1, 2 and 3, Bocrepresents tert-butoxycarbonyl group; Z represents benzyloxycarbonylgroup; pMZ represents 4-methoxybenzyloxycarbonyl group; Moc representsmethoxycarbonyl group; Fmoc represents 9-fluorenylmethoxycarbonyl group;Tfa represents trifluoroacetyl group; Tos represents p-toluene sulfonylgroup; Mts represents 2,4,6-trimethylbenzene sulfonyl group; Trtrepresents trityl group; and Pht represents phthalyl group.

                                      TABLE 1                                     __________________________________________________________________________    Comp.                                                                         No. R.sup.1                                                                           R.sup.2                                                                           R.sup.5      R.sup.6                                                                             R.sup.10  R.sup.11  R.sup.9                    __________________________________________________________________________    1   Boc H   H            H                                                                                    ##STR3##           H                          2   Boc H   CH.sub.3     H                                                                                    ##STR4##           H                          3   Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR5##           H                          4   Z   H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR6##           H                          5   Boc H   CH.sub.2 CH.sub.2 CH.sub.3                                                                 H                                                                                    ##STR7##           H                          6   Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR8##           H                          7   Boc  CH.sub.3                                                                         CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR9##           H                          8   Boc H                                                                                  ##STR10##   H                                                                                    ##STR11##          H                          9   Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H     CH.sub.3  CH.sub.3  H                          10  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H     CH.sub.2 CH.sub.3                                                                       CH.sub.2 CH.sub.3                                                                       H                          11  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR12##                                                                               ##STR13##                                                                              H                          12  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H     CH.sub.2 CH.sub.2   H                          13  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H     CH.sub.2 CH.sub.2 CH.sub.2                                                                        H                          14  Boc H   CH.sub.2 CH.sub.2 CH.sub. 2 CH.sub.3                                                       H                                                                                    ##STR14##          H                          15  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR15##          H                          16  Z   H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR16##          H                          17  pMZ H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR17##          H                          18  Fmoc                                                                              H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR18##          H                          19  Tos H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR19##          H                          20  Mts H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR20##          H                          21  Trt H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR21##          H                          22  Pht     CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR22##          H                          23  Boc H                                                                                  ##STR23##   H                                                                                    ##STR24##          H                          24  Boc H                                                                                  ##STR25##   H                                                                                    ##STR26##          H                          25  Boc H                                                                                  ##STR27##   H                                                                                    ##STR28##          H                          26  Boc H                                                                                  ##STR29##   H                                                                                    ##STR30##          H                          27  Boc H   CH.sub.3     CH.sub.3                                                                             ##STR31##          H                          28  Boc H   CH.sub.2 CH.sub.3                                                                          CH.sub.2 CH.sub.3                                                                    ##STR32##          H                          29  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                               ##STR33##          H                          30  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                      ##STR34##          H                          31  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR35##          CH.sub.3                   32  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR36##          CH.sub.3                   33  Boc H                                                                                  ##STR37##   H                                                                                    ##STR38##          CH.sub.3                   34  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR39##          CH.sub.2 CH.sub.3          35  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR40##          CH.sub.2 CH.sub.3          36  Boc H                                                                                  ##STR41##   H                                                                                    ##STR42##          CH.sub.2 CH.sub.3          37  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR43##          CH(CH.sub.3).sub.2         38  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR44##          CH(CH.sub.3).sub.2         39  Boc H                                                                                  ##STR45##   H                                                                                    ##STR46##          CH(CH.sub.3).sub.2         40  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR47##          CH.sub.2 CH.sub.2                                                             CH(CH.sub.3).sub.2         41  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR48##          CH.sub.2 CH.sub.2                                                             CH(CH.sub.3).sub.2         42  Boc H                                                                                  ##STR49##   H                                                                                    ##STR50##          CH.sub.2 CH.sub.2                                                             CH(CH.sub.3).sub.2         43  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR51##                                                                                         ##STR52##                 44  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR53##                                                                                         ##STR54##                 45  Boc H                                                                                  ##STR55##   H                                                                                    ##STR56##                                                                                         ##STR57##                 46  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR58##          CHCH.sub.2                 47  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR59##          CHCH.sub.2                 48  Boc H                                                                                  ##STR60##   H                                                                                    ##STR61##          CHCH.sub.2                 49  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR62##          CHCH(CH.sub.2).sub.3                                                          CH.sub.3 (trans)           50  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR63##          CHCH(CH.sub.2).sub.3                                                          CH.sub.3 (trans)           51  Boc H                                                                                  ##STR64##   H                                                                                    ##STR65##          CHCH(CH.sub.2).sub.3                                                          CH.sub.3 (trans)           52  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR66##          CHCH(CH.sub.2).sub.3                                                          CH.sub.3 (cis)             53  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR67##          CHCH(CH.sub.2).sub.3                                                          CH.sub.3 (cis)             54  Boc H                                                                                  ##STR68##   H                                                                                    ##STR69##          CHCH(CH.sub.2).sub.3                                                          CH.sub.3 (cis)             55  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR70##          CH.sub.2CHCH.sub.2         56  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR71##          CH.sub.2CHCH.sub.2         57  Boc H                                                                                  ##STR72##   H                                                                                    ##STR73##          CH.sub.2CHCH.sub.2         58  Boc H   H            H                                                                                    ##STR74##                                                                                         ##STR75##                 59  Boc H   CH.sub.3     H                                                                                    ##STR76##                                                                                         ##STR77##                 60  Boc H   CH(CH.sub.3).sub.2                                                                         H     CH.sub.3  CH.sub.3                                                                                 ##STR78##                 61  Boc H   CH(CH.sub.3).sub.2                                                                         H     CH.sub.2 CH.sub.3                                                                       CH.sub.2 CH.sub.3                                                                        ##STR79##                 62  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR80##                                                                               ##STR81##                                                                               ##STR82##                 63  Boc H   CH(CH.sub.3).sub.2                                                                         H     CH.sub.2 CH.sub.2                                                                                  ##STR83##                 64  Boc H   CH(CH.sub.3).sub.2                                                                         H     CH.sub.2 CH.sub.2 CH.sub.2                                                                         ##STR84##                 65  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR85##                                                                                         ##STR86##                 66  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR87##                                                                                         ##STR88##                 67  Z   H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR89##                                                                                         ##STR90##                 68  pMZ H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR91##                                                                                         ##STR92##                 69  Fmoc                                                                              H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR93##                                                                                         ##STR94##                 70  Tos H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR95##                                                                                         ##STR96##                 71  Mts H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR97##                                                                                         ##STR98##                 72  Trt H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR99##                                                                                         ##STR100##                73  Pht     CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR101##                                                                                        ##STR102##                74  Boc CH.sub.3                                                                          CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR103##                                                                                        ##STR104##                75  Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR105##                                                                                        ##STR106##                76  Boc H   CH.sub.2 CH.sub.2 CH.sub. 2 CH.sub.3                                                       H                                                                                    ##STR107##                                                                                        ##STR108##                77  Boc CH.sub.3                                                                          CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR109##                                                                                        ##STR110##                78  Boc H                                                                                  ##STR111##  H                                                                                    ##STR112##                                                                                        ##STR113##                79  Boc H                                                                                  ##STR114##  H                                                                                    ##STR115##                                                                                        ##STR116##                80  Boc H                                                                                  ##STR117##  H                                                                                    ##STR118##                                                                                        ##STR119##                81  Boc H                                                                                  ##STR120##  H                                                                                    ##STR121##                                                                                        ##STR122##                82  Boc H   CH.sub.3     CH.sub. 3                                                                            ##STR123##                                                                                        ##STR124##                83  Boc H   CH.sub.2 CH.sub.3                                                                          CH.sub.2 CH.sub.3                                                                    ##STR125##                                                                                        ##STR126##                84  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                               ##STR127##                                                                                        ##STR128##                85  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                      ##STR129##                                                                                        ##STR130##                86  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR131##                                                                                        ##STR132##                87  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR133##                                                                                        ##STR134##                88  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR135##                                                                                        ##STR136##                89  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR137##                                                                                        ##STR138##                90  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR139##                                                                                        ##STR140##                91  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR141##                                                                                        ##STR142##                92  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR143##                                                                                        ##STR144##                93  Boc H   CH.sub.2 CH.sub.2 CH.sub. 2 CH.sub.3                                                       H                                                                                    ##STR145##                                                                                        ##STR146##                94  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR147##                                                                                        ##STR148##                95  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR149##                                                                                        ##STR150##                96  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR151##                                                                                        ##STR152##                97  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR153##                                                                                        ##STR154##                98  Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR155##                                                                                        ##STR156##                99  Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR157##                                                                                        ##STR158##                100 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR159##                                                                                        ##STR160##                101 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR161##                                                                                        ##STR162##                102 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR163##                                                                                        ##STR164##                103 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR165##                                                                                        ##STR166##                104 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR167##                                                                                        ##STR168##                105 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR169##                                                                                        ##STR170##                106 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR171##                                                                                        ##STR172##                107 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR173##                                                                                        ##STR174##                108 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR175##                                                                                        ##STR176##                109 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR177##                                                                                        ##STR178##                110 Boc H   CH.sub.3     H                                                                                    ##STR179##                                                                                        ##STR180##                111 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR181##                                                                                        ##STR182##                112 Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR183##                                                                                        ##STR184##                113 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR185##                                                                                        ##STR186##                114 Boc H   CH.sub.3     H                                                                                    ##STR187##                                                                                        ##STR188##                115 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR189##                                                                                        ##STR190##                116 Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR191##                                                                                        ##STR192##                117 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR193##                                                                                        ##STR194##                118 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR195##                                                                                        ##STR196##                119 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR197##                                                                                        ##STR198##                120 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR199##                                                                                        ##STR200##                121 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR201##                                                                                        ##STR202##                122 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR203##                                                                                        ##STR204##                123 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR205##                                                                                        ##STR206##                124 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR207##                                                                                        ##STR208##                125 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR209##                                                                                        ##STR210##                126 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR211##                                                                                        ##STR212##                127 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR213##                                                                                        ##STR214##                128 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR215##                                                                                        ##STR216##                129 Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR217##                                                                                        ##STR218##                130 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR219##                                                                                        ##STR220##                131 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR221##                                                                                        ##STR222##                132 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR223##                                                                                        ##STR224##                133 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR225##                                                                                        ##STR226##                134 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR227##                                                                                        ##STR228##                135 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR229##                                                                                        ##STR230##                136 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR231##                                                                                        ##STR232##                137 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR233##                                                                                        ##STR234##                138 Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR235##                                                                                        ##STR236##                139 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR237##                                                                                        ##STR238##                140 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR239##         CH.sub.2 OH                141 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR240##         CH.sub.2 OH                142 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR241##                                                                                        ##STR242##                143 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR243##                                                                                        ##STR244##                144 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR245##                                                                                        ##STR246##                145 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR247##                                                                                        ##STR248##                146 Boc H   CH.sub.3     H                                                                                    ##STR249##                                                                                        ##STR250##                147 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR251##                                                                                        ##STR252##                148 Z   H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR253##                                                                                        ##STR254##                149 Fmoc                                                                              H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR255##                                                                                        ##STR256##                150 Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR257##                                                                                        ##STR258##                151 Boc H                                                                                  ##STR259##  H                                                                                    ##STR260##                                                                                        ##STR261##                152 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR262##                                                                                        ##STR263##                153 Boc H                                                                                  ##STR264##  H                                                                                    ##STR265##                                                                                        ##STR266##                154 Boc H                                                                                  ##STR267##  H                                                                                    ##STR268##                                                                                        ##STR269##                155 Boc H   CH.sub.3     H                                                                                    ##STR270##                                                                                        ##STR271##                156 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR272##                                                                                        ##STR273##                157 Boc H   CH.sub.2 CH(CH.sub.3).sub.2                                                                H                                                                                    ##STR274##                                                                                        ##STR275##                158 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR276##                                                                                        ##STR277##                159 Boc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR278##                                                                                        ##STR279##                160 Boc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR280##                                                                                        ##STR281##                161 Moc H   CH(CH.sub.3).sub.2                                                                         H                                                                                    ##STR282##                                                                                        ##STR283##                162 Moc H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                        H                                                                                    ##STR284##                                                                                        ##STR285##                __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Comp.                                                                         No.    R.sup.1                                                                              R.sup.2                                                                              R.sup.5         R.sup.6  R.sup.9                         __________________________________________________________________________    163    Boc    H      H               H        H                               164    H      H      H               H        H                               165    Boc    H      CH.sub.3        H        H                               166    H      H      CH.sub.3        H        H                               167    Boc    H      CH(CH.sub.3).sub.2                                                                            H        H                               168    H      H      CH(CH.sub.3).sub.2                                                                            H        H                               169    Z      H      CH(CH.sub.3).sub.2                                                                            H        H                               170    Boc    H      CH.sub.2 CH.sub.2 CH.sub.3                                                                    H        H                               171    H      H      CH.sub.2 CH.sub.2 CH.sub.3                                                                    H        H                               172    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        H                               173    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        H                               174    Boc    CH.sub.3                                                                             CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        H                               175    H      CH.sub.3                                                                             CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        H                               176    Boc    H                                                                                     ##STR286##     H        H                               177    H      H                                                                                     ##STR287##     H        H                               178    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               179    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               180    Z      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               181    pMZ    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               182    Fmoc   H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               183    Tos    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               184    Mts    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               185    Trt    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               186    Pht           CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        H                               187    Boc    H                                                                                     ##STR288##     H        H                               188    H      H                                                                                     ##STR289##     H        H                               189    Boc    H                                                                                     ##STR290##     H        H                               190    H      H                                                                                     ##STR291##     H        H                               191    Boc    H                                                                                     ##STR292##     H        H                               192    H      H                                                                                     ##STR293##     H        H                               193    Boc    H                                                                                     ##STR294##     H        H                               194    H      H                                                                                     ##STR295##     H        H                               195    Boc    H      CH.sub.3        CH.sub.3 H                               196    H      H      CH.sub.3        CH.sub.3 H                               197    Boc    H      CH.sub.2 CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                      H                               198    H      H      CH.sub.2 CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                      H                               199    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                                    H                               200    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                                    H                               201    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                           H                               202    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                           H                               203    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH.sub.3                        204    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH.sub.3                        205    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.3                        206    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.3                        207    Boc    H                                                                                     ##STR296##     H        CH.sub.3                        208    H      H                                                                                     ##STR297##     H        CH.sub.3                        209    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH.sub.2 CH.sub.3               210    H      H       CH.sub.2 CH(CH.sub.3).sub.2                                                                  H        CH.sub.2 CH.sub.3               211    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.2 CH.sub.3               212    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.2 CH.sub.3               213    Boc    H                                                                                     ##STR298##     H        CH.sub.2 CH.sub.3               214    H      H                                                                                     ##STR299##     H        CH.sub.2 CH.sub.3               215    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH(CH.sub.3).sub.2              216    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH(CH.sub.3).sub.2              217    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH(CH.sub.3).sub.2              218    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH(CH.sub.3).sub.2              219    Boc    H                                                                                     ##STR300##     H        CH(CH.sub.3).sub.2              220    H      H                                                                                     ##STR301##     H        CH(CH.sub.3).sub.2              221    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH.sub.2 CH.sub.2 CH(CH.sub.                                                  3).sub.2                        222    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH.sub.2 CH.sub.2 CH(CH.sub.                                                  3).sub.2                        223    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.2 CH.sub.2 CH(CH.sub.                                                  3).sub.2                        224    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.2 CH.sub.2 CH(CH.sub.                                                  3).sub.2                        225    Boc    H                                                                                     ##STR302##     H        CH.sub.2 CH.sub.2 CH(CH.sub.                                                  3).sub.2                        226    H      H                                                                                     ##STR303##     H        CH.sub.2 CH.sub.2 CH(CH.sub.                                                  3).sub.2                        227    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR304##                     228    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR305##                     229    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR306##                     230    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR307##                     231    Boc    H                                                                                     ##STR308##     H                                                                                       ##STR309##                     232    H      H                                                                                     ##STR310##     H                                                                                       ##STR311##                     233    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CHCH.sub.2                      234    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CHCH.sub.2                      235    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CHCH.sub.2                      236    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CHCH.sub.2                      237    Boc    H                                                                                     ##STR312##     H        CHCH.sub.2                      238    H      H                                                                                     ##STR313##     H        CHCH.sub.2                      239    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR314##                     240    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR315##                     241    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR316##                     242    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR317##                     243    Boc    H                                                                                     ##STR318##     H                                                                                       ##STR319##                     244    H      H                                                                                     ##STR320##     H                                                                                       ##STR321##                     245    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR322##                     246    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR323##                     247    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR324##                     248    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR325##                     249    Boc    H                                                                                     ##STR326##      H                                                                                      ##STR327##                     250    H      H                                                                                     ##STR328##     H                                                                                       ##STR329##                     251    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH.sub.2 CHCH.sub.2             252    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH.sub.2 CHCH.sub.2             253    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.2 CHCH.sub.2             254    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.2 CHCH.sub.2             255    Boc    H                                                                                     ##STR330##     H        CH.sub.2 CHCH.sub.2             256    H      H                                                                                     ##STR331##     H        CH.sub.2 CHCH.sub.2             257    Boc    H      H               H                                                                                       ##STR332##                     258    H      H      H               H                                                                                       ##STR333##                     259    Boc    H      CH.sub.3        H                                                                                       ##STR334##                     260    H      H      CH.sub.3        H                                                                                       ##STR335##                     261    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR336##                     262    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR337##                     263    Z      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR338##                     264    pMZ    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR339##                     265    Fmoc   H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR340##                     266    Tos    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR341##                     267    Mts    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR342##                     268    Moc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR343##                     269    Trt    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR344##                     270    Pht           CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR345##                     271    Boc    CH.sub.3                                                                             CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR346##                     272    H      CH.sub.3                                                                             CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR347##                     273    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR348##                     274    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR349##                     275    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR350##                     276    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR351##                     277    Boc    CH.sub.3                                                                             CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR352##                     278    H      CH.sub.3                                                                             CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR353##                     279    Boc    H                                                                                     ##STR354##     H                                                                                       ##STR355##                     280    H      H                                                                                     ##STR356##     H                                                                                       ##STR357##                     281    Boc    H                                                                                     ##STR358##     H                                                                                       ##STR359##                     282    H      H                                                                                     ##STR360##     H                                                                                       ##STR361##                     283    Boc    H                                                                                     ##STR362##     H                                                                                       ##STR363##                     284    H      H                                                                                     ##STR364##     H                                                                                       ##STR365##                     285    Boc    H                                                                                     ##STR366##     H                                                                                       ##STR367##                     286    H      H                                                                                     ##STR368##     H                                                                                       ##STR369##                     287    Boc    H      CH.sub.3        CH.sub.3                                                                                ##STR370##                     288    H      H      CH.sub.3        CH.sub.3                                                                                ##STR371##                     289    Boc    H      CH.sub.2 CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                       ##STR372##                     290    H      H      CH.sub.2 CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                       ##STR373##                     291    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                                     ##STR374##                     292    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                                     ##STR375##                     293    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                            ##STR376##                     294    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                            ##STR377##                     295    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR378##                     296    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR379##                     297    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR380##                     298    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR381##                     299    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR382##                     300    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR383##                     301    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR384##                     302    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR385##                     303    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR386##                     304    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR387##                     305    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR388##                     306    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR389##                     307    Boc    H      CH(CH.sub.3).sub.2                                                                             H                                                                                      ##STR390##                     308    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR391##                     309    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR392##                     310    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR393##                     311    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR394##                     312    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR395##                     313    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR396##                     314    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR397##                     315    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR398##                     316    H      H       CH(CH.sub.3).sub.2                                                                           H                                                                                       ##STR399##                     317    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR400##                     318    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR401##                     319    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR402##                     320    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR403##                     321    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR404##                     322    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR405##                     323    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR406##                     324    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR407##                     325    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR408##                     326    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR409##                     327    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR410##                     328    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR411##                     329    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR412##                     330    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR413##                     331    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR414##                     332    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR415##                     333    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR416##                     334    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR417##                     335    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR418##                     336    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR419##                     337    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR420##                     338    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR421##                     339    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR422##                     340    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR423##                     341    Boc    H      CH.sub.2 CH.sub.2 CH.sub. 2 CH.sub.3                                                          H                                                                                       ##STR424##                     342    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR425##                     343    Boc    H      CH.sub.3        H                                                                                       ##STR426##                     344    H      H      CH.sub.3        H                                                                                       ##STR427##                     345    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR428##                     346    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR429##                     347    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR430##                     348    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR431##                     349    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR432##                     350    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR433##                     351    Boc    H      CH.sub.3        H                                                                                       ##STR434##                     352    H      H      CH.sub.3        H                                                                                       ##STR435##                     353    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR436##                     354    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR437##                     355    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR438##                     356    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR439##                     357    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR440##                     358    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR441##                     359    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR442##                     360    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR443##                     361    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR444##                     362    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR445##                     363    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR446##                     364    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR447##                     365    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR448##                     366    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR449##                     367    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR450##                     368    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR451##                     369    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR452##                     370    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR453##                     371    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR454##                     372    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR455##                     373    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR456##                     374    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR457##                     375    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR458##                     376    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR459##                     377    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR460##                     378    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR461##                     379    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR462##                     380    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR463##                     381    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR464##                     382    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR465##                     383    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR466##                     384    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR467##                     385    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR468##                     386    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR469##                     387    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR470##                     388    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR471##                     389    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR472##                     390    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR473##                     391    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR474##                     392    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR475##                     393    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR476##                     394    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR477##                     395    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR478##                     396    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR479##                     397    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR480##                     398    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR481##                     399    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR482##                     400    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR483##                     401    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR484##                     402    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR485##                     403    Boc    H      CH(CH.sub.3).sub.2                                                                            H        CH.sub.2 OH                     404    H      H      CH(CH.sub.3).sub.2                                                                            H        CH.sub.2 OH                     405    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.2 OH                     406    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        CH.sub.2 OH                     407    Boc    H      CH(CH.sub.3).sub.2                                                                            H        CH(CH.sub.3)OH                  408    H      H      CH(CH.sub.3).sub.2                                                                            H        CH(CH.sub.3)OH                  409    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH(CH.sub.3)OH                  410    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        CH(CH.sub.3)OH                  411    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR486##                     412    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR487##                     413    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR488##                     414    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR489##                     415    Boc    H      CH.sub.3        H        C(CH.sub.3).sub.2 OH            416    H      H      CH.sub.3        H        C(CH.sub.3).sub.2 OH            417    Boc    H      CH(CH.sub.3).sub.2                                                                            H        C(CH.sub.3).sub.2 OH            418    H      H      CH(CH.sub.3).sub.2                                                                            H        C(CH.sub.3).sub.2 OH            419    Z      H      CH(CH.sub.3).sub.2                                                                            H        C(CH.sub.3).sub.2 OH            420    Fmoc   H      CH(CH.sub.3).sub.2                                                                            H        C(CH.sub.3).sub.2 OH            421    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        C(CH.sub.3).sub.2 OH            422    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H        C(CH.sub.3).sub.2 OH            423    Boc    H                                                                                     ##STR490##     H        C(CH.sub.3).sub.2 OH            424    H      H                                                                                     ##STR491##     H        C(CH.sub.3).sub.2 OH            425    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H        C(CH.sub.3).sub.2 OH            426    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.                                                            H        C(CH.sub.3).sub.2 OH            427    Boc    H                                                                                     ##STR492##     H        C(CH.sub.3).sub.2 OH            428    H      H                                                                                     ##STR493##     H        C(CH.sub.3).sub.2 OH            429    Boc    H                                                                                     ##STR494##     H        C(CH.sub.3).sub.2 OH            430    H      H                                                                                     ##STR495##     H        C(CH.sub.3).sub.2 OH            431    Boc    H      CH.sub.3        H                                                                                       ##STR496##                     432    H      H      CH.sub.3        H                                                                                       ##STR497##                     433    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR498##                     434    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR499##                     435    Boc    H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR500##                     436    H      H      CH.sub.2 CH(CH.sub.3).sub.2                                                                   H                                                                                       ##STR501##                     437    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR502##                     438    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR503##                     439    Boc    H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR504##                     440    H      H      CH(CH.sub.3).sub.2                                                                            H                                                                                       ##STR505##                     441    Boc    H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR506##                     442    H      H      CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                           H                                                                                       ##STR507##                     __________________________________________________________________________

    TABLE 3      Comp. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.10     R.sup.11 R.sup.9                443 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H      ##STR508##      H  444 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H CH.sub.3 CH.sub.3 H 445 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H     CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.3 CH.sub.2     CH.sub.3 H  446 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2     CH.sub.2      CH.sub.3 H     ##STR509##      ##STR510##      H  447 Boc  H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H CH.sub.2 CH.sub.2 H 448 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H     CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.2 CH.sub.2 H  449     Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     H      ##STR511##      H  450 Z H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR512##      H  451 Fmoc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR513##      H  452 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR514##      H      453 Boc H     ##STR515##      H CH.sub.2 CH.sub.2 CH.sub.2      CH.sub.3 H     ##STR516##      H      454 Boc H     ##STR517##      H CH.sub.2 CH.sub.2 CH.sub.2      CH.sub.3 H     ##STR518##      H      455 Boc H CH.sub.3 H     ##STR519##      H      ##STR520##      H      456 Boc H CH(CH.sub.3).sub.2 H     ##STR521##      H      ##STR522##      H  457 Boc H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR523##      H      ##STR524##      H  458 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR525##      CH.sub.3  459 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2     CH.sub.2      CH.sub.3 H     ##STR526##      CHCH.sub.2      460 Boc H     ##STR527##      H CH.sub.3 H      ##STR528##      ##STR529##      461 Boc H CH.sub.3 H CH(CH.sub.3).sub.2 H     ##STR530##      ##STR531##      462 Boc H CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.3 H     ##STR532##      ##STR533##                 463 Boc H CH.sub.2 CH(CH.sub.3 ).sub.2 H CH(CH.sub.3).sub.2     H CH.sub.3 CH.sub.3      ##STR534##       464 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 (CH.sub.3).sub.2 H     CH.sub.2 CH.sub.3 CH.sub.2      CH.sub.3     ##STR535##       465 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 (CH.sub.3).sub.2 H      ##STR536##      ##STR537##      ##STR538##                466 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     CH.sub.2      CH.sub.2     ##STR539##       467 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2      CH.sub.2     ##STR540##       468 Boc H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR541##      ##STR542##       469 Boc H CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H      ##STR543##      ##STR544##       470 Boc CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H      ##STR545##      ##STR546##       471 Boc CH.sub.3 CH.sub.2      CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H      ##STR547##      ##STR548##       472 Z H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR549##      ##STR550##       473 Fmoc H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR551##      ##STR552##        474 Boc H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR553##      ##STR554##       475 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH(CH.sub.3).sub.2 H      ##STR555##      ##STR556##      476 Boc H     ##STR557##      H CH(CH.sub.3).sub.2 H      ##STR558##      ##STR559##      477 Boc H     ##STR560##      H CH(CH.sub.3).sub.2 H      ##STR561##      ##STR562##       478 Boc H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR563##      ##STR564##       479 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR565##      ##STR566##       480 Z H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR567##      ##STR568##      481 Boc H CH(CH.sub.3).sub.2 H     ##STR569##      H      ##STR570##      ##STR571##       482 Boc H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR572##      H      ##STR573##      ##STR574##       483 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR575##      ##STR576##       484 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR577##      ##STR578##       485 Boc H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR579##      ##STR580##       486 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H      ##STR581##      ##STR582##       487 Boc H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR583##      H      ##STR584##      ##STR585##       488 Boc H CH.sub.2      CH(CH.sub.3).sub. 2 H CH(CH.sub.3).sub.2 H     ##STR586##      ##STR587##

The process for the production of the compounds of the present inventionwill now be explained. The cyclopropene derivatives of the presentinvention may be produced, for example, by the following process:

Process 1: A process for producing a compound represented by the abovegeneral formula (I) wherein R⁷ and R⁸ represent --OR¹⁰ and --OR¹¹,respectively: ##STR588## (In the above general formula, R¹, R², R³, R⁴,R⁵, R⁶, R⁹, R¹⁰, R¹¹ and n are those as defined above.)

Using the known process described in the reference (Tetrahedron Letters,Vol.32, pp.1339, 1991), cyclopropenone ketal derivative represented bythe above general formula (II) is readily synthesized. The derivative isdissolved in an ethereal solvent such as tetrahydrofuran, diethylether,etc., followed by addition of a strong base such as n-butyl lithium,methyl lithium, lithium diisopropylamide in the presence of an additivesuch as tetramethylethylenediamine, hexamethylphosphoric triamide,1,3-dimethyl-2-imidazolidone, etc. to prepare a lithiated compoundthereof. Then, an aldehyde derivative represented by the above generalformula (III) is added to the resulting lithiated compound to preparethe cyclopropene derivative represented by the above general formula(1-a). In the reaction, anhydrous cerium chloride suspension in asolvent such as tetrahydrofuran, diethylether, hexane and the like mayfurther be added to the lithiated compound of the resulting compound(II) to transform the compound into the cerium salt thereof, with whichthe aldehyde derivative represented by the general formula (III) may bereacted.

Process 2: A process for producing a compound represented by the abovegeneral formula (I) wherein R⁷, taken together with R⁸ represents ═O,and n is zero: ##STR589## (In the above general formula, R¹, R², R⁵, R⁶,R⁹, R¹⁰, and R¹¹ are those as defined above.)

The cyclopropene derivative represented by the above general formula(I-a)', produced by the process of Process 1, is dissolved in acetone,diethyl ether, tetrahydrofuran, etc., followed by treatment with an ionexchange resin such as Amberlist 15 (registered trade mark) or followedby addition of a mineral acid such as dilute sulfuric acid to effectselective deprotection of ketal, whereby the cyclopropene derivativerepresented by the above general formula (I-b) is produced.

By the process described in Japanese Patent Application No. Hei4-146024, the cyclopropene derivative represented by the above generalformula (I) can be lead to cyclopropenone derivatives exhibiting astrong inhibitory activity against thiol protease such as calpain,papain, cathepsin B, cathepsin H, cathepsin L and the like.

The present invention will now be described in examples hereinbelow, butthe invention is not limited to the examples, unless departing from thespirit and scope of the invention.

EXAMPLE 1 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-phenylcyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 65 in Table 1)

To a solution of 3.51 g of 2-phenylcyclopropenone2,2-dimethyl-1,3-propanediyl acetal in 30 ml of tetrahydrofuran wasadded 3.8 g of N, N, N', N'-tetramethylethylenediamine. To the reactionsolution chilled at -78° C. was added a 1.55 ml/l solution of n-butyllithium in 10.5 ml of hexane, and the mixture was stirred for 20minutes. Then, 30 ml of tetrahydrofuran suspension of anhydrous ceriumchloride prepared by drying 8.0 g of cerium chloride heptahydrate at140° C./1 mmHg for 2 hours was added to the mixture, which was stirredfor 20 minutes. A solution of 1.82 g of N-tert-butoxycarbonyl-L-valinalin 20 ml of tetrahydrofuran was added, and the resultant mixture wasstirred at -78° C. for 2 hours. A solution of 1 ml of water in 5 ml oftetrahydrofuran was added to the reaction mixture, which was allowed towarm at room temperature and filtered through celite. The celite waswashed well with ethyl acetate, and the filtrate was dried over sodiumsulfate, filtered, concentrated and chromatographed on a column ofsilica gel, eluting with hexane containing 20% ethyl acetate as adeveloping solvent to give 2.71 g of the titled product.

Yield: 72% IR (KBr, cm⁻¹): 3430, 2960, 1855, 1800, 1710, 1690 NMR (CD₃OD, δ): 0.95-1.60 (m, 12H), 1.38 (s, 3H), 1.42 (s, 6H), 1.95-2.15 (m,1H), 3.60-3.75 (m, 1H), 3.75-3.95 (m, 4H), 5.0-5.10 (m, 1H), 6.03 (d,J=10 Hz, 0.33H), 6.23 (d, J=10 Hz, 0.67H), 7.40-7.65 (m, 3H), 7.70-7.90(m, 2H)

In the same manner as in Example 1, the following compounds wereproduced.

EXAMPLE 2 Preparation of2-(2-tert-butoxycarbonylamino-1-hydroxyethyl)cyclopropenone2,2-dimethyl-l,3-propanediyl acetal (Compound No. 1 in Table 1)

NMR (CDCl₃, δ): 0.97 (s, 3H), 1.09 (s, 3H), 1.44 (s, 9H), 3.35-3.60 (m,2B), 3.63 (s, 4H), 4.80-4.88 (m, 1H), 5.07-5.26 (m, 1H), 5.26-5.52 (m,1H), 7.63 (s, 1H)

EXAMPLE 3 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)cyclopropenone2,2-dimethyl-1-1,3-propanediyl acetal (Compound No. 3 in Table 1)

IR (neat, cm⁻¹): 3380, 1722, 1708, 1690 NMR (CDCl₃, δ): 0.87-1.10 (m,12H), 1.43 (s, 7.2H), 1.45 (s, 1.8H), 2.05-2.20 (m, 1H), 3.35-3.70 (m,5H), 4.80-5.03 (m, 2H), 7.57 (s, 0.8H), 7.71 (s, 0.2H)

EXAMPLE 4 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-4-methylpentyl)cyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 6 in Table 1)

IR (neat, cm⁻¹): 3445, 3360, 1705 NMR (CDCl₃, δ): 0.80-0.95 (m, 9H),1.15 is, 3B), 1.44 (s, 9H), 1.55-1.78 (m, 3H), 3.63 (s, 2H), 3.65 (s,2H), 3.72-3.95 (m, 1H), 4.70-4.84 (m, 2H), 5.02-5.15 (m, 1H), 7.68 (s,0.9H), 7.71 (s, 0.1H)

EXAMPLE 5 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)cyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 14 in Table 1)

IR (neat, cm⁻¹): 3460, 3370, 1700 NMR (CDCl₃, δ): 0.85-1.0 (m, 3H), 0.92(s, 3H), 1.14 (s, 3H), 1.25-1.55 (m, 6H), 1.44 (s, 9H), 3.05-3.15 (m,0.7H), 3.25-3.35 (m, 0.3H), 3.61 (s, 2H), 3.63 (s, 2H), 3.65-3.85 (m,0.7H), 3.85-4.05 (m, 0.3H), 4.70-4.85 (m, 1H), 4.85-4.95 (m, 0.3H),5.0-5.15 (m, 0.7H), 7.65 (s, 0.7H), 7.72 (s, 0.3H)

EXAMPLE 6 Preparation of2-((2S)-2-benzyloxycarbonylamino-1-hydroxyhexyl)cyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 16 in Table 1)

IR (neat, cm⁻¹): 3360, 1723 NMR (CDCl₃, δ): 0.75-0.98 (m, 6H), 1.08 (s,1.5H), 1.12 (s, 1.5H), 1.18-1.60 (m, 6H), 3.04 (s, 0.5H), 3.32 (d, J=7.8Hz, 0.5H), 3.55-3.70 (m, 4H), 3.80 (m, 0.5H), 4.01 (m, 0.5H), 4.76 (d,J=7.8 Hz, 0.5H), 4.83 (m, 0.5H), 5.11 (s, 2H), 5.13 (m, 0.5H), 5.63 (d,J=8.1 Hz, 0.5H), 7.65 (s, 0.5H), 7.73 (s, 0.5H)

EXAMPLE 7 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-methylcyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 32 in Table 1)

NMR (CDCl₃, δ): 0.84-0.96 (m, 3H), 0.95 (s, 3H), 1.08 (s, 3H), 1.28-1.55(m, 6H), 1.43 (s, 9H), 2.17 (s, 3H), 3.53-3.80 (m, 5H), 4.63-4.74 (m,1H), 4.88-5.07 (m, 1H)

EXAMPLE 8 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-4-methylpentyl)-3-ethylcyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 34 in Table 1)

IR (neat, cm⁻¹): 3360, 1853, 1696, 1623 NMR (CDCl₃, δ): 0.88-1.01 (m,12H ), 1.32 (t, J=7.7 Hz, 3H), 1.37-1.55 (m, 2H), 1.41 (s, 9H),1.60-1.78 (m, 1H), 2.69 (q, J=7.7 Hz, 2H), 3.55-3.70 (m, 4H), 3.79-4.02(m, 1H), 4.67-4.78 (m, 1H), 4.80-5.03 (m, 1H), 5.16 -5.22 (m, 1H)

EXAMPLE 9 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-isopentylcyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 41 in Table 1)

IR (neat, cm⁻¹): 3360, 1816,,1715, 1698 NMR (CDCl₃, δ): 0.78-0.98 (m,12H), 1.11 (s, 3H), 1.18-1.77 (m, 9H), 1.43 (s, 9H), 2.53 (d, J=7.6 Hz,2H), 3.56-3.80 (m, 5H), 4.65-4.80 (m, 1H), 4.98-5.12 (m, 1H)

EXAMPLE 10 Preparation of 2-((1S,2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-((Z)-1-hexenyl)cyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 53 in Table 1)

IR (neat, cm⁻¹): 3440, 1785, 1703 NMR (CDCl₃, δ): 0.80-0.97 (m, 9H),1.19 (s, 3H), 1.21-1.80 (m, 10H), 1.43 (s, 9H), 2.35-2.50 (m, 2H), 2.82(s, 1H), 3.57-3.82 (m, 5H), 4.66-4.85 (m, 2H), 5.82-6.06 (m, 2H)

EXAMPLE 11 Preparation of2-[(2S)-2-(N-tert-butoxycarbonyl)methylamino-1-hydroxy-3-methylbutyl]-3-phenylcycloprene2,2-dimethyl-1,3-propanediyl acetal (Compound No. 74 in Table 1)

IR (KBr, cm⁻¹): 3430, 1798, 1688, 1672 NMR (CD₃ OD, δ): 0.80-1.35 (m,12H), 1.45 (s, 9H), 2.30 (m, 1H), 2.69 (s, 1.5H), 2.72 (s, 1.5H),3.65-3.90 (m, 4H), 4.09 (m, 1H), 5.02 (m, 1H), 7.30-7.52 (m, 3H),7.70-7.82 (m, 2H)

EXAMPLE 12 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-phenylcyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 76 in Table 1)

IR (KBr, cm⁻¹): 3310, 1800, 1720, 1792 NMR (CDCl₃, δ): 0.80-0.98 (m,3H), 0.99 (s, 3H), 1.21 (s, 3H), 1.15-1.90 (m, 6H), 1.39 (s, 2.7H), 1.43(s, 6.3H), 3.58 (m, 0.7H), 3.68-4.95 (m, 4.6H), 4.95-4.10 (m, 0.7H),4.88-5.07 (m, 1.3H), 5.24 (d, J=7.4 Hz, 0.7H), 7.28-7.45 (m, 3H), 7.69(d, J=6.5 Hz, 2H)

EXAMPLE 13 Preparation of2-(2-tert-butoxycarbonylamino-1-hydroxy-2-methylpropyl)-3-phenylcyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 82 in Table 1)

IR (KBr, cm⁻¹): 3290, 1800, 1673 NMR (CDCl₃, δ): 0.94 (s, 3H), 1.25 (s,3H), 1.27 (s, 9H), 1.41 (s, 3H), 1.64 (s, 3H), 3.70-3.90 (m, 4H), 4.77(d, J=8.6 Hz, 1H), 4.93 (s, 1H), 5.57 (s, 1H), 7.28-7.46 (m, 3H), 7.75(dd, J=8.2 Hz, 1.4 Hz, 2H )

EXAMPLE 14 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-(4-fluorophenyl)cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 90 inTable 1 )

IR (KBr, cm⁻¹): 3340, 1802, 1710, 1695, 1602 NMR (CD₃ OD, δ): 0.90-1.25(m, 12H), 1.38 (s, 6.3H), 1.42 (s, 2.7H), 2.08 (m, 1H), 3.63 (m, 1H),3.70-3.93 (m, 4H), 5.08 (d, J=4.5 Hz, 0.3H), 5.02 (d, J=4.5 Hz, 0.7H),6.05 (d, J=10 Hz, 0.3H), 6.19 (d, J=10 Hz, 0.7H), 7.18-7.30 (m, 2H),7.70-7.88 (m, 2H)

EXAMPLE 15 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-(2-tolyl)cyclopropenone2,2-dimethyl-1,3propanediyl acetal (Compound No. 105 in Table 1)

NMR (CDCl₃, δ): 0.83-1.03 (m, 3H), 0.96 (s, 3H), 1.25 (s, 3H), 1.25-1.51(m, 4H), 1.40 (s, 1.8H), 1.43 (s, 7.2H), 1.60-1.95 (m, 2H), 2.45 (s,0.6H), 2.52 (s, 2.4H), 3.65-3.90 (m, 1H), 3.73 (s, 4H), 4.80-5.20 (m,2H), 7.05-7.30 (m, 3H), 7.55-7.65 (m, 1H)

EXAMPLE 16 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-(5-trimethylsilyl-2-furyl)cyclopenone2,2dimethyl-1,3-propandiyl acetal (Compound No. 130 in Table 1)

NMR (CDCl₃, δ): 0.28 (s, 9H), 0.85-0.95 (m, 6H), 1.22 (s, 3H), 1.21-1.85(m, 15H), 3.65-4.05 (m, 5H), 4.80-5.20 (m, 3H), 6.70 (d, J=3.9 Hz, 1),6.78 (d, J=3.9 Hz, 1H)

EXAMPLE 17 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-(5-trimethylsilyl-2-thienyl)cyclopropenone2,2dimethyl-1,3-propanediyl acetal (Compound No. 139 in Table 1)

NMR (CDCl₃, δ): 0.34 (s, 9H), 0.84-0.97 (m, 6H), 1.24 (s, 3H), 1.27-1.50(m, 13H), 1.55-1.92 (m, 2H), 3.64-4.04 (m, 5H), 4.83-5.30 (m, 2H), 7.21(d, J=3.4 Hz, 1H), 7.38 (d, J=3.4 Hz, 1H)

EXAMPLE 18 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-(1-hydroxy-1-methylbutyl)-3-(hydroxy-1-methylethyl)cyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 147 in Table 1)

NMR (CDCl₃, δ): 0.92-1.07 (m, 12H), 1.41-1.53 (m, 15H), 1.80-2.05 (m,1H), 3.56-3.78 (m, 5H), 4.84-4.90 (m, 1H), 5.10 (d, J=11 Hz, 0.3H), 5.26(d, J=11 Hz, 0.7H), 6.0 (s, 2H)

EXAMPLE 19 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-[(hydroxy)(phenyl)methyl]cyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 156 in Table 1)

NMR (CDCl₃, δ): 0.86-1.12 (m, 12H), 1.36-1.48 (m, 9H), 1.77-2.05 (m,1H), 3.40-3.78 (m, 5H), 4.82-4.92 (m, 1H), 5.24-5.42 (m, 1H), 5.67-5.74(m, 2H), 5.98 (s, 1H), 7.25-7.50 (m, 5H)

EXAMPLE 20 Preparation of2-((2S)-2-methoxycarbonylamino-3-methyl1-hydroxybutyl)-3-phenylcyclopropenone2,2-dimethyl-1,3-diyl acetal (Compound No. 161 in Table 1)

IR (KBr, cm⁻¹): 3436, 3378, 1858, 1792, 1703, 1626 NMR (CD₃ OD, δ):0.88-1.35 (m, 12H), 1.90-2.15 (m, 1H), 3.55-3.90 (m, 8H), 4.95 (d, J=5.2Hz, 0.2H), 4.98 (d, J=5.0 Hz, 0.8H), 7.32-7.55 (m, 3H), 7.60-7.83 (m,2H)

EXAMPLE 21 Preparation of2-[(2S)-2-((2S)-2-benzyloxycarbonylamino-3-methylvalerylamino)-1-hydroxyhexyl)-3-(4-fluorophenyl)cyclopropenone2,2-dimethyl-1,3-propanediyl acetal (Compound No. 490 in Table 3)

IR (KBr, cm⁻¹): 3320, 1802, 1710, 1660, 1602 NMR (CD₃ OD, δ): 0.70-1.18(m, 15H), 1.18-1.95 (m, 9H), 3.66-3.90 (m, 4H), 4.02-4.30 (m, 2H), 4.95(m, 1H), 5.02 (s, 2H), 7.10-7.40 (m, 7H), 7.40-7.60 (m, 1H), 7.70-7.83(m, 2H)

EXAMPLE 22 Preparation of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone(Compound No. 178 in Table 2)

To a solution of 8.80 g of2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone2,2-dimethyl-1.3-propanediyl acetal obtained in Example 5 in 100 ml ofdiethyl ether and 20 ml of tetrahydrofuran were added 0.2 ml of 2 Nsulfuric acid and 1 ml of water, and the mixture was stirred for 30minutes. After subsequent addition of 300 ml of ether, the resultingproduct was washed sequentially in 50 ml of an aqueous 0.01 N sodiumhydroxide solution and an aqueous saturated brine. After drying overmagnesium sulfate, the product was filtered and concentrated, followedby purification by silica gel column chromatography (eluent; hexane:ethyl acetate =1:2) to produce the objective product (3.15 g).

Yield: 47% IR (neat, cm⁻¹): 3440, 1835, 1700 NMR (CDCl₃, δ): 0.85-1.9(m, 3H), 1.25-1.85 (m, 6H), 1.42 (s, 9H), 2.60-2.90 (m, 1H), 3.75-3.95(m, 1H), 4.75-4.85 (m, 0.8H), 4.85-4.95 (m, 0.2H), 5.19 (d, J=9 Hz, 1H),8.59 (s, 0.8H), 8.65 (s, 0.2H)

In the same manner as in Example 22, the following compounds wereproduced.

EXAMPLE 23 Preparation of 2-(2-tert-Butoxycarbonylamino-1-hydroxyethyl)cyclopropenone (Compound No. 163 in Table 2)

IR (neat, cm⁻¹): 3350, 1840, 1718, 1700 NMR (CDCl₃, δ): 1.44 (s, 9H),3.43-3.70 (m, 2H), 4.84-4.97 (m, 2H), 5.15-5.70 (m, 1H), 8.63 (s, 1H)

EXAMPLE 24 Preparation of2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-methylbutyl)cyclopropenone (Compound No. 167 in Table 2)

IR (KBr, cm⁻¹): 3330, 1838, 1820, 1712, 1690, 1678 NMR (CDCl₃, δ): 1.02(d, J=7.2 Hz, 2.1H), 1.05 (d, J=7.3 Hz, 2.1H), 1.08 (d, J=7.3 Hz, 0.9H),1.11 (d, J=7.3 Hz, 0.9H), 1.41 (s, 6.3H), 1.43 (s, 2.7H), 1.90-2.05 (m,0.3H), 2.15-2.33 (m, 0.7), 3.40 (m. 0.7H), 3.68 (m, 0.3H), 4.87-4.98 (m,1H), 5.02-5.16 (m, 2H), 8.57 (s, 0.7H), 8.66 (s, 0.3H)

EXAMPLE 25 Preparation of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-4-methylpentyl)cyclopropenone(Compound No. 172 in Table 2 )

IR (neat, cm⁻¹): 3350, 1833, 1700 NMR (CDCl₃, δ): 0.86-0.98 (m, 6H),1.43 (s, 9H), 1.55-1.83 (m, 3H), 3.88-4.06 (m, 1H), 4.70-4.86 (m, 1H),5.12-5.38 (m, 1H), 8.61 (s, 0.75H), 8.66 (s, 0.25H)

EXAMPLE 26 Preparation of2-((2S)-2-benzyloxycarbonylamino-1hydroxyhexyl) cyclopropenone (CompoundNo. 190 in Table 2)

IR (neat, cm⁻¹): 3440, 3350, 1840, 1715 NMR (CDCl₃, δ): 0.82-0.98 (m,3H), 1.26-1.80 (m, 6H), 3.85-4.05 (m, 1H), 4.76-4.84 (m, 1H), 4.86-4.93(m, 0.4H), 5.02-5.16 (m, 2.6H), 5.27 (d, J=7.8 Hz, 0.4H), 5.47 (d, J=7.7Hz, 0.6H), 8.44 (s, 0.4H), 8.49 (s, 0.6H)

EXAMPLE 27 Preparation of2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-phenylpropyl)cyclopropenone(Compound No. 199 in Table 2)

IR (KBr, cm⁻¹): 3265, 1838, 1700 NMR (CDCl₃, δ): 1.41 (s, 6.3H), 1.43(s, 2.7H), 2.80-3.18 (m, 2H), 3.94-4.25 (m, 1H), 4.65-4.77 (m, 1H),4.82-4.95 (m, 0.3H), 5.15-5.25 (m, 0.7H), 5.30-5.42 (m, 0.7H), 5.50-5.60(m, 0.3H), 7.13-7.35 (m, 5H), 8.43 (s, 0.7H), 8.51 (s, 0.3H)

EXAMPLE 28 Preparation of2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-methylcyclopropenone(Compound No. 215 in Table 2)

NMR (CDCl₃, δ): 0.87-0.96 (m, 3H), 1.28-1.50 (m, 2H), 1.41 (s, 9H),1.50-1.82 (m, 4H), 2.32 (s, 3H), 3.68-3.82 (m, 0.6H), 3.82-3.93 (m,0.4H), 4.67-4.82 (m, 1.4H), 4.87-5.0 (m, 0.4H), 5.02-5.14 (m, 0.6H),5.44 (d, J=6.8 Hz, 0.6H )

EXAMPLE 29 Preparation of2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-4-methylpentyl)-3-ethylcyclopropenone(Compound No. 219 in Table 2)

IR (neat, cm⁻¹): 3360, 1852, 1696, 1622 NMR (CDCl₃, δ): 0.90 (d, J=7.2Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.28 (t, J=7.7 Hz, 3H), 1.42 (s, 9H),1.40-1.58 (m, 2H), 1.60-1.78 (m, 1H), 2.63 (q, J=7.7 Hz, 2H), 3.70-3.85(m, 1H), 4.60-4.75 (m, 1H), 4.75-4.90 (m, 1H), 5.0-5.18 (m, 1H)

EXAMPLE 30 Preparation of2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-isopentylcyclopropenone(Compound No. 233 in Table 2)

IR (neat, cm⁻¹): 3320, 1842, 1707, 1683, 1620 NMR (CDCl₃, δ): 0.83-0.98(m, 9H), 1.28-1.85 (m, 9H), 1.41 (s, 9H), 2.66 (q, J=7.2 Hz, 2H),3.67-3.95 (m, 1H), 4.60-4.70 (m, 1H), 4.70-4.78 (m, 1H), 4.98-5.08 (m,1H)

EXAMPLE 31 Preparation of 2-((1S, 2S )-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-((Z)-1-hexenyl)cycloplopropenone (Compound No. 257 in Table 2)

IR (neat, cm⁻¹): 3270, 1842, 1710 , 1690, 1635 NMR (CDCl₃, δ): 0.80-0.97(m, 6H), 1.25-1.83 (m, 10H), 1.40 (s, 9H), 2.59 (q, J=7.0 Hz, 2H), 3.75(m, 1H), 4.70 (m, 1H), 4.79 (d, J=4.7 Hz, 1H), 5.01 (d, J=8.6 Hz, 1H),6.26 (d, J=11 Hz, 1H), 6.40-6.55 (m, 1H)

EXAMPLE 32 Preparation of2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-phenylcyclopropenone(Compound No. 285 in Table 2)

NMR (CDCl₃, δ): 0.86-0.97 (m, 3H), 1.28-1.51 (m, 4H), 1.31 (s, 1.8H),1.34 (s, 7.2H), 1.52-1.93 (m, 2H), 3.73-3.88 (m, 0.8H), 3.93-4.03 (m,0.2H), 4.84 (d, J=6.8 Hz, 0.2H), 4.91-5.03 (m, 1H), 5.12-5.27 (m, 1.6H),5.73 (d, J=8.1 Hz, 0.2H), 7.42-7.60 (m, 3H), 7.95-8.05 (m, 2H)

EXAMPLE 33 Preparation of2-((2S)-2-tert,Butoxycarbonylamino-1-hydroxyhexyl)-3-(2-tolyl)cyclopropenone (Compound No. 343 in Table 2 )

NMR (CDCl₃, δ): 0.85-0.96 (m, 3H), 1.28-1.51 (m, 13H), 1.53-1.95 (m,2H), 2.68 (s, 3H), 3.72-3.88 (m, 0.7H), 3.94-4.05 (m, 0.3H), 4.75-5.18(m, 2.7H), 5.59 (d, J=8.1 Hz, 0.3H), 7.25-7.34 (m, 2H), 7.38-7.47 (m,1H), 8.07-8.16 (m, 1H)

EXAMPLE 34 Preparation of2((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-(5-trimethylsilyl-2-thienyl)cyclopropenone(Compound No. 411 in Table 2)

NHR (CDCl₃, δ): 0.34 (s, 2.7H), 0.35 (s, 6.3H), 0.86-0.97 (m, 3H),1.25-1.52 (m, 4H), 1.32 (s. 2.7H), 1.35 (s, 6.3H), 1.53-1.92 (m, 2H),3.68-3.82 (m, 0.7H), 3.92-4.02 (m, 0.3H), 4.65-5.09 (m, 2.7H), 5.69 (d,J=7.7 Hz, 0.3H), 7.28 (d, J=4.1 Hz, 0.3H), 7.29 (d, J=4.1 Hz, 0.7H),7.82 (d, J=4.1 Hz, 1H)

EXAMPLE 35 Preparation of2((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-(1-hydroxy-1-methylethyl)cyclopropenone(Compound No. 427 in Table 2)

IR (neat, cm⁻¹): 3430, 3300, 1840, 1683, 1628 NMR (CDCl₃, δ): 0.98 (d,J=6.8 Hz, 1.8H), 1.04 (d, J=6.8 Hz, 1.8H), 1.05 (d, J=6.7 Hz, 1.2H),1.10 (d, J=6.8 Hz, 1.2H), 1.41 (s, 5.4H), 1.43 (s, 3.6H), 1.48-1.57 (m,6H), 1.90-2.12 (m, 1H), 3.65-3.80 (m, 1H), 4.20 (s, 0.4H), 4.76 (d,J=7.7 Hz, 0.4H), 4.85-4.17 (m, 2.8H), 5.59 (m, 0.4H)

EXAMPLE 36 Preparation of2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3[(hydroxy)(phenyl)methyl]cyclopropenone(Compound No. 443 in Table 2)

IR (neat, cm⁻¹): 3440, 3330, 1845, 1716, 1683, 1630 NMR (CDCl₃, δ):0.96-1.11 (m, 6H), 1.18 (s, 1.9H), 1.37 (s, 1.0H), 1.39 (s, 3.6H), 1.43(s, 2.5H), 1.90-2.15 (m, 1H), 3.68-3.78 (m, 0.3H), 3.78-3.89 (m, 0.7H),4.89-5.40 (m, 1H), 5.16 (d, J=11 Hz, 0.7H), 5.40 (d, J=11 Hz, 0.3H),5.30-5.41 (m, 1H), 5.62 (d, J=9.2 Hz, 0.3H), 5.80 (d, J=9.2 Hz, 0.7H),5.86 (s, 1H), 7.50-7.86 (m, 3H), 7.86-8.11 (m, 2H)

EXAMPLE 37 Preparation of 2-((2S)-2-amino-1-hydroxyhexyl) cyclopropenonep-toluene sulfonate (Compound No. 179 in Table 2)

To 5 ml of a dichloroethane solution of 150 mg of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl) cyclopropenoneobtained in Example 22 was added 106 mg of p-toluene sulfonatemonohydrate. After stirring at room temperature for 5 hours, the solventwas distilled off under reduced pressure to give 250 mg of the titledproduct.

NMR (CD₃ OD, δ): 0.93-1.10 (m, 3H), 1.30-1.65 (m, 4H), 1.65-2.05 (m,2H), 2.41 (s, 3H), 3.40-3.60 (m, 0.7H), 3.60-3.75 (m, 0.3H), 4.89 (d,J=4 Hz, 0.7H), 5.15 (d, J=4 Hz, 0.3H), 7.28 (d, J=8 Hz, 2H), 7.74 (d,J=8 Hz, 2H), 9.12 (s, 0.7H), 9.18 (s, 0.3H)

EXAMPLE 38 Preparation of2-((2S)-2-amino-l-hydroxy-3-methylbutyl)-3-phenylcyclopropenonehydrochloride (Compound No. 262 in Table 2)

To 8 ml of a dioxane solution of 3.12 g of2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-phenylcyclopropenone2,2-dimethyl, 1,3-propanediyl acetal obtained in Example 1 was added 24ml of a dioxane solution containing 4 N HCl, and the mixture was stirredfor 20 minutes. The resulting crystal was filtered and washed withdioxane, to give 1.87 g of the titled product.

Yield: 94% IR (KBr, cm⁻¹): 3200, 2975, 1855, 1618, 1510, 1450, 1055,770, 690 NMR (CD3OD, 8): 1.21 (t, J=7 Hz, 4.5H), 1.24 (t, J=7 Hz, 1.5H),2.0-2.2 (m, 0.25H), 2.2-2.4 (m, 0.75H), 3.38 (t, J=6 Hz, 0.25H), 3.45(t, J=6 Hz, 0.75H), 5.21 (d, J=6 Hz, 0.75H), 5.45 (d, J=6 Hz, 0.25H),7.60-7.80 (m, 3H), 8.10-8.20 (m, 2H)

In the same manner as in Examples 37 and 38, the following compoundswere produced.

EXAMPLE 39 Preparation of 2-((1S,2S)-2-amino-1-hydroxy-4-methylpentyl)cyclopropenone p-toluene sulfonate(Compound No. 173 in Table 2)

NMR (CD₃ OD, δ): 1.02 (d, J=6.2 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H),1.60-1.95 (m, 3H), 2.42 (s, 3H), 3.58 (m, 1H), 4.88 (d, J=4.9 Hz, 1H),7.31 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H), 9.11 (s, 1H)

EXAMPLE 40 Preparation of2-((2S)-2-amino-1-hydroxy-3-phenylpropyl)cyclopropenone p-toluenesulfonate (Compound No. 200 in Table 2)

NMR (CD₃ OD, δ): 2.41 (s, 3H), 3.03-3.30 (m, 2H), 3.80-4.10 (m, 1H),4.75-5.00 (m, 1H), 7.15 -7.45 (m, 7H), 7.75 (d, J=8.1 Hz, 2H), 8.88 (s,0.3H), 9.04 (s, 0.7H)

EXAMPLE 41 Preparation of2-((2S)-2-amino-1-hydroxy-4-methylpentyl)-3-ethylcyclopropenonep-toluene sulfonate (Compound No. 220 in Table 2)

NMR (CD₃ OD, δ): 0.95-1.15 (m, 6H), 1.55-1.95 (m, 3H), 2.41 (s, 3H),2.68-2.88 (m, 2H), 3.40-3.60 (m, 1H), 4.75-4.85 (m, 1H), 7.27 (d, J=8.0Hz, 2H), 7.75 (d, J=8.0 Hz, 2H)

EXAMPLE 42 Preparation of 2-((1S,2S)-2-amino-1-hydroxyhexyl-3-((E)-1-hexenyl) cyclopropenone p-toluenesulfonate (Compound No. 252 in Table 2)

IR (KBr, cm⁻¹): 3422, 1845, 1630, 1601 NMR (CD₃ OD, δ): 0.80-1.05 (m,6H), 1.20-1.95 (m, 10H), 2.36 (s, 3H), 2.32-2.40 (m, 2H), 3.25-3.45 (m,1H), 4.82 (d, J=7.3 Hz, 1H), 6.38 (d, J=16 Hz, 1H), 7.02 (dd, J=16 Hz,7.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H)

EXAMPLE 43 Preparation of 2-((1S,2S)-2-amino-1-hydroxyhexyl)-3-((Z)-1-hexenyl) cyclopropenone p-toluenesulfonate (Compound No. 258 in Table 2)

IR (neat, cm⁻¹): 3260, 1845, 1633 NMR (CDCl₃, δ): 0.73 (t, J=7.1 Hz,3H), 0.89 (t, J=6.7 Hz, 3H), 1.08-1.95 (m, 10H), 2.35 (s, 3H), 2.40-2.65(m, 2H), 3.33 (m, 1H), 3.92 (s, 3H), 4.88 (m, 1H), 6.21 (d, J=10 Hz,1H), 6.40 (dd, J=10 Hz, 6.8 Hz, 1H), 7.14 (d, J=6.7 Hz, 2H), 7.71 (d,J=6.7 Hz, 2H), 7.81 (m, 1H)

EXAMPLE 44 Preparation of2-((2S)-1-hydroxy-3-methyl-2-methylaminobutyl)-3-phenylcyclopropenonehydrochloride (Compound No. 282 in Table 2)

IR (KBr, cm⁻¹): 3422, 1858, 1626 NMR (CD₃ OD, δ: 0.78-0.95 (m, 6H),2.05-2.40 (m, 1H), 2.79 (s, 3H), 3.47 (m, 1H), 5.28 (d, J=4.5 Hz, 0.5H),5.43 (d, J=4.4 Hz, 0.5H), 7.55-7.75 (m, 3H), 7.95-8.13 (m, 2H)

EXAMPLE 45 Preparation of2-(2-amino-1-hydroxy-2-methylpropyl)-3-phenylcyclopropenonehydrochloride (Compound No. 298 in Table 2 )

IR (KBr, cm⁻¹): 3300, 3250, 1858, 1620 NMR (CD₃ OD, δ): 1.42 (s, 3H),1.57 (s, 3H), 4.98 (s, 1H), 7.55-7.78 (m, 3H), 8.07 (d, J=7.3 Hz, 2H)

EXAMPLE 46 Preparation of2-((2S)-2-amino-1-hydroxy-3-methylbutyl)-3-(1-hydroxy-1-methylethyl)cyclopropenone hydrochloride (Compound No. 428 in Table 2)

IR (KBr, cm⁻¹): 3420, 1846, 1615 NMR (CD₃ OD, δ: 1.09 (d, J=6.9 Hz,2.1H), 1.13 (d, J=6.9 Hz, 2.1H), 1.14 (s, 1.8H), 1.56 (s, 4.2H), 1.58(s, 1.8H), 1.99 (m, 0.3H), 2.15 (m, 0.7H), 3.25 (m, 0.3H), 3.39 (m,0.7H), 5.01 (d, J=5.5 Hz, 0.7H), 5.19 (d, J=4.5 Hz, 0.3H)

EXAMPLE 47 Preparation of2-((2S)-2-amino-1-hydroxy-3-methylbutyl)-(4-fluorophenyl) cyclopropenone(Compound No. 314 in Table 2)

IR (KBr, cm⁻¹): 3280, 1858, 1620, 1600 NMR (CD₃ OD, δ): 1.05-1.33 (m,6H), 2.07 (m, 0.2H), 2.29 (m, 0.8H), 3.38 (m, 0.2H), 3.44 (m, 0.8H),5.20 (d, J=6.1 Hz, 0.8H), 5.41 (d, J=4.7 Hz, 0.2H), 7.38-7.52 2H),8.15-8.32 (m, 2H)

EXAMPLE 48 Preparation of2-((2S)-2-amino-1-hydroxy-3-methylbutyl)-3-[(hydroxy)(phenyl)methyl]cyclopropenonehydrochlorine (Compound No. 444 in Table 2)

IR (KBr, cm⁻¹): 3430, 1846, 1626 NMR (CD₃ OD, δ): 1.0-1.20 (m, 6H),1.90-2.22 (m, 1H), 3.20-3.45 (m, 1H), 5.0-5.25 (m, 1H), 5.97 (s, 0.75H),6.0 (s, 0.25H), 7.28-7.45 (m, 3H), 7.45-7.60 (m, 2H)

EXAMPLE 49 Preparation of2-((2S)-2-methoxycarbonylamino-3-methyl-1-hydroxybutyl)-3-phenylcyclopropenone(Compound No. 278 in Table 2)

IR (neat, cm⁻¹): 3333, 1856, 1705, 1622 NMR (CDCl₃, δ): 0.95-1.15 (m,6H), 1.95-2.40 (m, 1H), 3.56 (s, 2.4H), 3.63 (s, 0.6H), 3.72 (m, 0.2H),3.80 (m, 0.8H), 5.09 (d, J=4.5 Hz, 1H), 5.72 (d, J=6.7 Hz, 1H),7.45-7.60 (m, 3H), 7.93-8.08 (m, 2H)

What we claim is:
 1. Cyclopropene derivatives represented by formula(I): ##STR590## wherein: R¹ represents hydrogen atom or a protectivegroup for an amino group; R² represents hydrogen atom, a protectivegroup for an amino group or a C₁ -C₅ alkyl group;R⁴ and R⁶ independentlyrepresent a hydrogen atom or C₁ -C₅ alkyl group; R³ and R⁵ independentlyrepresent a hydrogen atom or C₁ -C₁₅ alkyl group optionally substitutedwith C₃ -C₁₀ cycloalkyl group or C₆ -C₁₀ aryl group; or when R⁵ and R⁶are taken together, they represent a C₂ -C.sub. 6 alkylene group; R⁷ andR⁸ represent --OR¹⁰ and --OR¹¹, respectively, wherein R¹⁰ and R¹¹independently represent C₁ -C₅ alkyl group optionally substituted withphenyl group; or when R¹⁰ and R¹¹ are taken together, they represent aC₂ -C₆ alkylene group optionally substituted with one or more C₁ C₅alkyl groups; or when R⁷ and R⁸ are taken together, they represent ═O;R⁹ represents a hydrogen atom, C₁ -C₁₅ alkyl group, C₃ -C₁₀ cycloalkylgroup, C₂ -C₁₅ alkenyl group, C₆ -C₁₀ aryl group optionally substitutedwith one or more substituents selected from the group consisting ofhalogen atom, C₁ -C₅ alkyl group, hydroxyl group and C₁ -C₅ alkoxygroup, heterocyclic selected from the group consisting of thienyl andfuryl, optionally substituted with one or more substituents selectedfrom the group consisting of C₃ -C₁₂ trialkylsilyl group, halogen atom,C₁ -C₅ alkyl group, hydroxyl group and C₁ -C₅ alkoxy group, or --CR¹²R¹³ OH wherein R¹² and R¹³ independently represent a hydrogen atom, C₁-C₅ alkyl group or C₆ -C₁₀ aryl group; or when R¹² and R¹³ are takentogether they represent a C₃ -C₁₀ cycloalkyl group; and n represents 0.2. Compounds according to claim 1, wherein R¹ represents hydrogen atom,tert-butoxycarbonyl group, benzyloxycarbonyl group, methoxycarbonylgroup, 9-fluorenylmethoxycarbonyl group, p-toluene sulfonyl group, ortrityl group; R², R⁴ and R⁶ independently represent hydrogen atom or C₁-C₃ alkyl group; R³ and R⁵ independently represent hydrogen atom or C₁-C₅ alkyl group optionally substituted with C₃ -C₈ cycloalkyl group,phenyl group or naphthyl group; or R⁵, when taken together with R⁶represents C₂ -C₅ alkylene group; R⁷ and R⁸ represent --OR¹⁰ and --OR¹¹,respectively wherein, R¹⁰ and R¹¹ independently represent C₁ -C₃ alkylgroup optionally substituted with phenyl group; or R¹⁰ when takentogether with R¹¹ represents C₂ -C₄ alkylene group optionallysubstituted with one or more C₁ -C₃ alkyl groups; or R⁷,when takentogether with R⁸ represents ═O; R⁹ represents hydrogen atom; C₁ -C₆alkyl group; C₃ -C₈ cycloalkyl group; C₂ -C₈ alkenyl group; phenyl groupor naphthyl group each optionally substituted with one or moresubstituents selected from the group consisting of halogen atom, C₁ -C₅alkyl group and C₁ -C₅ alkoxy group; heterocyclic selected from thegroup consisting of thienyl and furyl, optionally substituted with oneor more substituents selected from the group consisting of halogen atom,C₁ -C₅ alkyl group, C₁ -C₅ alkoxy group, and C₃ -C₁₂ trialkylsilylgroup; or --CR¹² R¹³ OH wherein R¹² and R¹³ independently representhydrogen atom, C₁ -C₃ alkyl group or phenyl group.
 3. Compoundsaccording to claim 1, wherein R¹ represents hydrogen atom,tert-butoxycarbonyl group, benzyloxycarbonyl group or methoxycarbonylgroup; R², R⁴ and R⁶ independently represent hydrogen atom or C₁ -C₃alkyl group; R³ and R⁵ independently represent hydrogen atom or C₁ -C₅alkyl group optionally substituted with phenyl group; R⁷ and R⁸represent --OR¹⁰ and --OR¹¹, respectively, wherein R¹⁰, when takentogether with R¹¹ represents C₂ -C₄ alkylene group optionallysubstituted with one or more C₁ -C₃ alkyl groups; or R⁷,when takentogether with R⁸ represents ═O; R⁹ represents hydrogen atom; C₁ -C₆alkyl group; C₂ -C₈ alkenyl group; phenyl group optionally substitutedwith one or more substituents selected from the group consisting ofhalogen atom and C₁ -C₅ alkyl group; furyl group or thienyl group eachoptionally substituted with one or more C₃ -C₁₂ trialkylsilyl groups; or--CR¹² R¹³ OH wherein R¹² and R¹³ independently represent hydrogen atom,C₁ -C₃ alkyl group or phenyl group.